Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13]N=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[CH3:33][N:34]=[C:35]=[O:36]>>[CH3:33][NH:34][C:35]([N:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:11]2[CH:2]=[CH:13][C:14]([C:15](=[O:16])[C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])=[C:9]([NH2:8])[N:10]=2)[CH2:28][CH2:29]1)=[O:36]
Reactant: CN=C=O
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Product: CNC(=O)N1CCC(Nc2ccc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The title compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt (Example 22) and methyl isocyanate (Aldrich, 98%) using the procedure described in Example 24. HRMS, observed: 402.1940, Calcd for (M+H)+: 402.1936.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][Si:38]([CH3:45])([CH3:44])[CH2:39][CH2:40][O:41][CH2:42]Cl>CN(C=O)C.O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[N:21]([CH2:42][O:41][CH2:40][CH2:39][Si:38]([CH3:45])([CH3:44])[CH3:37])[C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17]([N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCCn1c(N2CCCC2)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(N2CCCC2)nc2nc(-c3cnn(Cc4ccccc4)c3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
A mixture of 8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-one (0.83 g, 2.1 mmol) and potassium carbonate (0.857 g, 6.2 mmol) was taken in DMF (5 ml) and 2-(trimethylsilyl)ethoxymethyl chloride (1.0 ml, 6.2 mmol) was added drop wise at 0° C. and the mixture was stirred at 20° C. for 4 hours. The mixture was cooled to 10° C. and diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate (3×15 ml). The organic layer was washed with saturated brine solution (2×15 ml) and dried over Na2SO4. Solvent was evaporated and the residue was further purified by column chromatography to obtain the above product as pale yellow semisolid (0.325 g, 30%)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH:15]4C[CH2:16]4)=[N:13][N:14]=C3C[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3Cl)[C:6]=2[CH:25]=1.C([NH:29]N)CC.C(O)CO[CH2:34][CH2:35][OH:36]>>[NH2:29][C:7]([NH2:8])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]1[CH:25]=[CH:2][CH:3]=[CH:4][C:5]=1[N:11]1[C:12]([CH2:15][CH3:16])=[N:13][N:14]=[C:34]1[CH:35]=[O:36]
Reactant: OCCOCCO
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(C3CC3)n1-2
Reactant: CCCNN
Product: CCc1nnc(C=O)n1-c1ccccc1C(N)(N)c1ccccc1

Procedure:
In the manner given in Examples 1-7, above, 1ethyl-6-phenyl-4H-s-triazolo[ 4,3-a][1,4]benzodiazepine (III) in diethylene glycol is treated with propyl hydrazine to obtain both A and B 4-[α-amino-α-amino-α-phenyl-o-tolyl]-5-ethyl -4H-1,2,4-triazole-3-carboxaldehyde, propylhydrazone, which is separated by column chromatography into the two diastereomers A and B.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[S:7][C:8]=1[C:9](=[N:11][OH:12])[CH3:10].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23](S(C)(=O)=O)[N:22]=1>CN(C=O)C>[Cl:3][C:4]1[N:5]=[C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[S:7][C:8]=1[C:9](=[N:11][O:12][C:23]1[N:24]=[C:25]([O:27][CH3:28])[CH:26]=[C:21]([O:20][CH3:19])[N:22]=1)[CH3:10]
Reactant: CC(=NO)c1sc(-c2cccnc2)nc1Cl
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(ON=C(C)c2sc(-c3cccnc3)nc2Cl)n1
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (NaH, 60% dispersion in mineral oil: 48 mg, 1.2 mmol) in DMF (2 ml) was added a solution of 1-[4-chloro-2-(3-pyridyl)thiazol-5-yl]ethanone oxime (253.7 mg, 1 mmol) in DMF (3 ml), and the resulting frothy mixture was stirred for 1 hour. After that, 4,6-dimethoxy-2-methylsulfonyl-pyrimidine (218 mg, 1 mmol) was added into the above solution. The homogeneous, dark-red solution was stirred at ambient temperature for 18 hours. The precipitated brown solid was filtered and washed with water and dried under vacuum to afford the brown solid of 1-[4-chloro-2-(3-pyridyl)thiazol-5-yl]-N-(4,6-dimethoxypyrimidin-2-yl)oxy-ethanimine in a mixture of Z and E-isomers. 1H NMR (300 Mz, CDCl3): δ: 9.16 (s, 1H), 8.70 (d, 1H, J=4.8 Hz), 8.24 (m, 1H), 7.41 (m, 1H), 5.84 (m, 1H), 3.97 (m, 6H), 2.79 (m, 2H). MS (ESI): 392 (M+1), 414 (M+Na).
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[F:10][C:9]1[C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: O=Cc1cccc(F)c1F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cccc(F)c1N1CCOCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A 100 mL round-bottom flask was charged with 2,3-difluorobenzaldehyde (2.00 g, 14.1 mmol, 1.00 equiv), morpholine (1.84 g, 21.1 mmol, 1.50 equiv), potassium carbonate (4.90 g, 35.4 mmol, 2.52 equiv), and dimethyl sulfoxide (20 mL). The resulting solution was stirred overnight at 100° C. in an oil bath and diluted with H2O (50 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with H2O (3×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/20) to yield 0.840 g (28% yield) of 3-fluoro-2-(morpholin-4-yl)benzaldehyde as a yellow solid. 1H NMR 300 MHz, (CDCl3) δ 10.54 (s, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.18-7.34 (m, 2H), 3.85 (br, 4H), 3.23 (br, 4H). LCMS (ESI, m/z): 210 [M+H].
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=O)[CH3:2].ClCCCl.C(O)[C:40]1[CH:45]=[CH:44]C=[CH:42][CH:41]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>CCCCCC.C(OCC)(=O)C>[C:9]([O:8][C@H:7]1[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:18][C@@H:5]([O:4][CH2:1][C:2]2[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=2)[C@@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=[O:11])[CH3:10]
Reactant: OCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
Under anhydrous conditions, 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranose (5) (47.7 g, 100 mM), molecular sieves (4 Å) powder (20 g) and 250 ml of 1,2-dichloroethane and benzyl alcohol (12.5 ml, 120 mM) were placed in a dry 1 liter round bottom flask equipped with magnetic stirring bar, septum inlet and bent tube adapter. During a 5 minute period, trimethylsilyl trifluoromethane sulfonate (19.3 ml, 100 mM) was then added to the stirred mixture. The contents were stirred at room temperature for 16 hours. The reaction was found to be complete as evidenced by the products present on thin layer chromtography (TLC, 2:3 ethyl acetate:hexane). The reaction mixture was cooled in an ice-bath, quenched with saturated sodium bicarbonate and extracted with dichloromethane in the manner well known to those skilled in the art. The combined extract was washed with water, brine and dried over anhydrous magnesium sulfate. The residue after removal of solvent was purified by "flash chromatography" (silica gel, 500 g, solvent 1:3 ethyl acetate:hexane) to provide 40.6 g (85% yield) of benzyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranoside (6).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9]CC)=O.[CH3:24][N:25](C=O)C.C(O)=O>C(N)=O.C(O)(C)C>[C:12]1([C:4]2[NH:3][C:2]3[N:1]=[CH:24][N:25]=[C:7]([OH:9])[C:6]=3[CH:5]=2)[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(-c2ccc(-c3ccccc3)cc2)[nH]c1N
Solvent: O=CO
Solvent: CC(C)O
Solvent: NC=O
Product: Oc1ncnc2[nH]c(-c3ccc(-c4ccccc4)cc3)cc12

Procedure:
766 mg (2.5 mmol) of 2-amino-3-ethoxycarbonyl-5-(biphen-4-yl)-1H-pyrrole are stirred in 5 ml of formamide, 2.5 ml of DMF and 1.25 ml of formic acid for 20 h at 150° C. The reaction mixture is diluted with isopropanol and filtered. Washing with isopropanol and hexane yields the title compound; m.p.>300° C.; FAB-MS: (M+H)+ =288.
Reaction SMILES: Br[C:2]1[N:6](COCC[Si](C)(C)C)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:3]=1[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].CO[CH2:35][CH2:36][O:37][CH3:38]>>[CH3:38][O:37][C:36]1[C:5]([NH2:6])=[N:4][CH:3]=[C:2]([C:2]2[N:6]=[C:5]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:4][C:3]=2[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[CH:35]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccccc2)nc(-c2ccncc2)c1Br
Reactant: COCCOC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc(-c2nc(-c3ccccc3)[nH]c2-c2ccncc2)cnc1N
Temperature: 90 °C
Yield: 33 %

Procedure:
A mixture of 4-(5-bromo-2-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridine (620 mg, 1.4 mmol; Example 1, Step 3), 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)pyridine-2-amine (570 mg, 2.3 mmol, Example 17, Step 3), and aqueous 2.0 M Na2CO3 solution (2 mL, 4 mmol) in DME (8 mL) was purged with Ar for 3 min. Pd(dppf) Cl2-DCM (34 mg, 0.04 mmol) was added and the reaction mixture was purged with Ar for another 5 min. The reaction mixture was then heated to and maintained at 90° C. for 18 h under Ar. The reaction was allowed to cool to rt and was concentrated. The resulting residue was suspended in EtOAc (15 mL) and passed through a syringe filter. The filtrate was concentrated, treated with aqueous 3 M HCl solution (6 mL), and heated at 60° C. for 2 h. The reaction was allowed to cool to rt and was evaporated in vacuo. The resulting residue was purified by reverse-phase HPLC and lypholized to afford 160 mg (33%) of 3-methoxy-5-(2-phenyl-5-(pyridine-4-yl)-1H-imidazol-4-yl)pyridine-2-amine as the TFA salt: LCMS (m/z): 344.2 (MH+); tR=0.46 min; 1H NMR (CD3OD) δ 3.88 (s, 3H), 6.22 (br s, 2H), 7.16 (m, 1H), 7.38 (t, J=7.2 Hz, 1H), 7.47 (t, J=7.2 Hz, 2H), 7.61 (m, 2H), 7.67 (m, 1H), 8.05 (d, J=6.0 Hz, 2H), 8.48 (d, J=6.0 Hz, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH:6]([F:7])[C:5]2[C:8]([Cl:15])=[CH:9][CH:10]=[C:11]([N+:12]([O-])=O)[C:4]=2[NH:3]1.[Sn](Cl)Cl.[CH2:20](O)C>>[O:1]=[S:2]1(=[O:16])[C:6]([F:7])([CH3:20])[C:5]2[C:8]([Cl:15])=[CH:9][CH:10]=[C:11]([NH2:12])[C:4]=2[NH:3]1
Reactant: CCO
Reactant: O=[N+]([O-])c1ccc(Cl)c2c1NS(=O)(=O)C2F
Agent: Cl[Sn]Cl
Product: CC1(F)c2c(Cl)ccc(N)c2NS1(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To the solution of 1,3-dihydro-2,2-dioxo-4-chloro-3-fluoro-7-nitro-2,1-benzisothiazole (100 mg, 0.4 mmol) in ethanol (10 ml), Tin (II) chloride (443 mg, 2.0 mmol) was added. The reaction mixture was stirred at room temperature for about 16 hours. Then all solvent was evaporated. Chromatography of the residue on silica gel (50% Ethyl acetate/Hexane) gave desired product (43 mg, 47%). EI-MS m/z 237.2 (M+).
Reaction SMILES: [N:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].[Cl:12][CH2:13][C:14]1[N:15]=[CH:16][N:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH:18]=1>>[ClH:12].[Cl:26][C:21]1[CH:20]=[C:19]([N:17]2[CH:18]=[C:14]([CH2:13][N:1]3[C:5]4[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=4[N:3]=[CH:2]3)[N:15]=[CH:16]2)[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: c1nc2c([nH]1)CCCC2
Reactant: ClCc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Agent: [H-]
Agent: [Na+]
Product: Cl
Product: Clc1ccc(-n2cnc(Cn3cnc4c3CCCC4)c2)cc1Cl

Procedure:
Reaction of 4,5,6,7-tetrahydrobenzimidazole with sodium hydride followed by treatment with 4-chloromethyl-1-(3,4-dichloro-phenyl)-1H-imidazole led after extractive workup and chromatography to the free base of the title compound which was converted into its white hydrochloride salt. Mp. >250° C. (MeOH/Et2O), MS: m/e=346 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:12]=2[N:11]=[CH:10]1.S(=O)(=O)(O)O.[CH2:26](O)[CH3:27]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]([O:20][CH2:26][CH3:27])=[O:19])=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:4]=1
Reactant: CCO
Reactant: O=C(O)c1ccc2c(c1)ncn2-c1cc(Cl)ccc1O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2c(c1)ncn2-c1cc(Cl)ccc1O

Procedure:
A mixture of 4a (170 mg, 0.59 mmol), conc. sulfuric acid (3 mg, 0.029 mmol), and 99% ethanol (10 ml) was refluxed for 1 h. Silica gel was added to the mixture and the solvent was evaporated. The silica gel containing the crude product was put on top of a silica gel column and the product was eluated by methylene chloride/ethanol (9:1). Yield 120 mg, mp>360° C.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:21]=[CH:20][C:12]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].C(O)C.Cl>O>[CH:1]1([CH2:7][NH:8][C:9]2[CH:21]=[CH:20][C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCc1ccc(NCC2CCCCC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCc1ccc(NCC2CCCCC2)cc1

Procedure:
A 4 g. sample of ethyl 4-[(cyclohexyl)methylamino]hydrocinnamate is hydrolyzed with 1.6 g. 85% potassium hydroxide in 60 ml. 95% ethanol by refluxing the solution for 5 hours. The solution is cooled, diluted with 100 ml. water and acidified to pH 4.5 with 37% hydrochloric acid. The precipitate is collected, dried in vacuo and crystallized from acetone to yield the title compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].[Cl:25][C:26]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:27]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][OH:41])=[O:31].C(N(CC)CC)C.C1COCC1>CCOCC>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][O:32][C:30](=[O:31])[CH2:29][O:28][C:27]1[CH:42]=[CH:43][C:44]([Cl:46])=[CH:45][C:26]=1[Cl:25])=[O:11]
Reactant: O=C(COc1ccc(Cl)cc1Cl)OCCOCCOCCO
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(COc1ccc(Cl)cc1Cl)OCCOCCOCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
5-(2-Chloro-4-trifluoromethylphenoxy)-2-nitrobenzoyl chloride (4.0 g, 0.0105 mole) was added portionwise to a solution of 8-hydroxy-3,6-dioxaoctyl 2,4-dichlorophenoxyacetate (3.5 g, 0.103 mole), triethylamine (1.2 g, 0.103 mole) and THF (40 ml) over 5 mins. The resulting solution was held at reflux for 3 hrs. After the solvent was stripped off, the residue was taken into 2600 ml of ether, washed two times with NaHCO3 solution and two times with water. The ether solution was then dried over MgSO4 and concentrated to 5.9 g of 8-(2,4-dichlorophenoxyacetoxy)-3,6-dioxaoctyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate, a brownish gum; nmr (CDCl3) δ3.30-4.02 (m, 8H), 4.25-4.62 (m, 4H), 4.70 (S, 2H), 6.65-8.24 (m, 9H); ir (CHCl3) 1750, 1770 Cm-1.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Li]CCCC.[C:20]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[O:28])([O:22][CH3:23])=[O:21].[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1>[CH2:9]([N:8]([CH2:11][CH3:12])[C:6]([C:5]1[CH:13]=[CH:14][C:2]([CH:27]([OH:28])[C:26]2[CH:25]=[C:24]([CH:31]=[CH:30][CH:29]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:3][CH:4]=1)=[O:7])[CH3:10]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: CCN(CC)C(=O)c1ccc(I)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc(C(O)c2cccc(C(=O)OC)c2)cc1
Temperature: -78 °C
Yield: 48.8 %

Procedure:
INTERMEDIATE 5 (2.8 g, 9.0 mmol) was dissolved in TBF (100 mL) and cooled to −78° C. under nitrogen atmosphere. Then n-BuLi (8.4 mL, 1.07 M solution in hexane, 9.0 mmol) was added dropwise during 10 min at −65 to −78° C. The solution was canulated into 3-carbomethoxybenzaldehyde (1.49 g, 9.1 mmol) in toluene/THF (approx. 1:1, 50 mL) at −78° C. NH4Cl (aq.) was added after 30 min. After concentration in vacuo, extraction with EtOAc/water, drying (MgSO4) and evaporation of the organic phase, the residue was purified by chromatography on silica (0-75% EtOAc/heptane) to give INTERMEDIATE 6 (1.5 g, 49%).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6]N1CCN(C2C=CC=CC=2OC)CC1)#N.[CH:24]1([Mg]Cl)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[O:32]1CCCC1>C(OCC)C>[CH:24]1([C:6]([CH:5]2[CH2:4][CH2:3][CH2:23][CH2:22][CH2:21]2)=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1ccccc1N1CCN(Cc2cccc(C#N)c2)CC1
Reactant: Cl[Mg]C1CCCCC1
Reactant: C1CCOC1
Solvent: CCOCC
Product: O=C(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 1-(3-cyanobenzyl)-4-(2-methoxyphenyl)piperazine (5.60 g, 18.2 mmol) in 250 mL of tetrahydrofuran was added a solution of cyclohexylmagnesium chloride in ethyl ether (27.3 mL, 2.0M) under nitrogen. The solution was slowly warmed to 25° C. and then brought to reflux. After 48 h of reflux, thin layer chromatography indicated that the reaction was complete. The reaction mixture was then cooled to 0° C., ice cold 6N HCl solution (200 mL) was added, and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was then poured into a separatory funnel and washed with ether. The aqueous layer was then basified with K2CO3 and then extracted with chloroform. The organic extracts were combined, dried (Na2SO4), and concentrated to provide a dark green-brown oil. This material was purified on flash silica gel (1% methanol-chloroform) to afford 7.88 g (quantitative yield) of expected cyclohexyl ketone as a brown oil whose 1H NMR in CDCl3 was consistent with the desired structure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([CH:28]=[CH2:29])=[N:20][N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:15]=2[CH:14]=1.I[C:31]1[CH:32]=[N:33][N:34]([CH2:36][CH2:37][O:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH:35]=1.ClCCl.O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](/[CH:28]=[CH:29]/[C:31]3[CH:32]=[N:33][N:34]([CH2:36][CH2:37][O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)[CH:35]=3)=[N:20][N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:15]=2[CH:14]=1
Reactant: Ic1cnn(CCOC2CCCCO2)c1
Reactant: C=Cc1nn(C2CCCCO2)c2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ncc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2cc3c(cn2)c(/C=C/c2cnn(CCOC4CCCCO4)c2)nn3C2CCCCO2)c1Cl
Temperature: 95 °C
Reaction time: 3 h
Yield: 50.9 %

Procedure:
To a solution of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[4,3-c]pyridine (0.1 mmol) in DMF (0.5 mL) was added 4-iodo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazole (44 mg, 0.14 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (7.5 mg, 0.0092 mmol), and water (0.05 mL). The mixture was degassed and sealed. It was stirred at 95° C. for 3 h. After cooling the solid was filtered off, washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (32 mg). LCMS (M+H)+=628.2/630.3.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[N:13][C:12](C(OCC)=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].O.NN>C(O)C>[CH2:1]([N:3]1[C:15]2[CH:14]=[N:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCOC(=O)c1cc2c3ccccc3n(CC)c2cn1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCn1c2ccccc2c2ccncc21
Yield: 101.9 %

Procedure:
Compound 31 (2.7 g, 10 mmol) was dissolved into ethanol (50 ml). 85% Hydrazine hydrate (15 ml) was added. The mixture was refluxed by heating for 6 h and concentrated to 30 ml in reduced pressure. After cooling, filtration, wash with ethanol, and natural drying in the air, white solids (2.0 g, 83%) were obtained. Samples for analysis could be recrystallized by 90% ethanol to obtain white flaring sheet-like crystals, mp 195-196° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH2:9][CH:8]=[C:7]([O:10][CH3:11])[CH2:6][CH:5]=1)[CH3:3].[CH2:12]([O:19][C:20](ON1C(=O)CCC1=O)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1COCC1>[CH2:12]([O:19][C:20]([NH:1][C@H:2]([C:4]1[CH2:9][CH:8]=[C:7]([O:10][CH3:11])[CH2:6][CH:5]=1)[CH3:3])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC1=CCC([C@H](C)N)=CC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC1=CCC([C@H](C)NC(=O)OCc2ccccc2)=CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of the above diene (31) in THF (250 mL) was added in one portion N-(benzyloxycarbonyloxy) -succinimide (40 g) (slightly exothermic) followed by after 15 min triethylamine (23 mL). The reaction was stirred for 16 h at room temperature, evaporated, taken up in ethyl acetate, washed with 1N Na2CO3, saturated NaCl, dried over MgSO4 and evaporated to give crude product (32). TLC Rf 0.26 (10% ethyl acetate, n-hexane); 1H NMR (CDCl3) δ1.24 (3H, d, J=7 Hz), 2.73(4H, br s), 3.55(3H, s), 4.27(1H, q), 4.64(1H, br s), 4.78(1H, br d), 5.12(2H, s), 5.64(1H, br s), 7.38 (5H, s).